MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex

Leukemia. 2012 Apr;26(4):778-87. doi: 10.1038/leu.2011.287. Epub 2011 Nov 8.

Abstract

Recently, strategies for acute myeloid leukemia (AML) therapy have been developed that target anti-apoptotic BCL2 family members using BH3-mimetic drugs such as ABT-737. Though effective against BCL2 and BCL-X(L), ABT-737 poorly inhibits MCL-1. Here we report that, unexpectedly, ABT-737 induces activation of the extracellular receptor activated kinase and induction of MCL-1 in AML cells. MEK inhibitors such as PD0325901 and CI-1040 have been used successfully to suppress MCL-1. We report that PD0325901 blocked ABT-737-induced MCL-1 expression, and when combined with ABT-737 resulted in potent synergistic killing of AML-derived cell lines, primary AML blast and CD34+38-123+ progenitor/stem cells. Finally, we tested the combination of ABT-737 and CI-1040 in a murine xenograft model using MOLM-13 human leukemia cells.Whereas control mice and CI-1040-treated mice exhibited progressive leukemia growth, ABT-737, and to a significantly greater extent, ABT-737+CI-1040 exerted major anti-leukemia activity. Collectively, results demonstrated unexpected anti-apoptotic interaction between the BCL2 family-targeted BH3-mimetic ABT-737 and mitogen-activated protein kinase signaling in AML cells: the BH3 mimetic is not only restrained in its activity by MCL-1, but also induces its expression. However, concomitant inhibition by BH3 mimetics and MEK inhibitors could abrogate this effect and may be developed into a novel and effective therapeutic strategy for patients with AML.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism*
  • Bcl-2-Like Protein 11
  • Benzamides / pharmacology
  • Biphenyl Compounds / pharmacology*
  • Cell Line, Tumor
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / physiology*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitrophenols / pharmacology*
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / analysis
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Sulfonamides / pharmacology*
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / physiology

Substances

  • ABT-737
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BAK1 protein, human
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Benzamides
  • Biphenyl Compounds
  • Mcl1 protein, mouse
  • Membrane Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitrophenols
  • PD 0325901
  • Piperazines
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • Diphenylamine
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases